Tobacco abuse among adolescents is a major health and economic concern, yet there is a critical knowledge gap regarding the mechanisms that mediate adolescent smoking behavior. Our preliminary data demonstrate that adolescent male rats display enhanced nicotine reward and reduced nicotine withdrawal relative to adults. This proposal extends our previous work by examining the neural mechanisms that mediate developmental sensitivity and sex differences in the behavioral .effects of nicotine reward and withdrawal. In order to study the long-term consequences produced by adolescent nicotine exposure, our proposal also includes adult rats pre-exposed to nicotine during adolescence. Nicotine reward is mediated in part by enhanced dopamine (DA) transmission in the nucleus accumbens (NAcc). In contrast, nicotine withdrawal produces a decrease in NAcc DA levels. Changes in NAcc DA transmission are mediated by excitatory and inhibitory systems that regulate DA projections that originate in the ventral tegmental area (VTA). During adolescence, excitatory systems that regulate DA are overdeveloped, whereas inhibitory systems are underdeveloped. We hypothesize that adolescents will display enhanced nicotine reward and reduced nicotine withdrawal relative to adults. These developmental differences are likely mediated via enhanced excitation and reduced inhibition of VTA DA cell bodies. Overall we expect that these differences will be magnified in female adolescents and nicotine pre-exposed rats. This is based on clinical studies demonstrating that teenage females and adults pre-exposed to nicotine during adolescence display enhanced vulnerability to long-term tobacco abuse. Behavioral studies will compare nicotine reward using place preference procedures and nicotine withdrawal using place aversion procedures. Neurochemical studies will employ in vivo microdialysis procedures to compare NAcc DA and concomitant measures of excitatory and inhibitory systems in the VTA following nicotine administration and during nicotine withdrawal. This research is significant because our findings may have significant implications towards guiding public policies regarding tobacco regulation and warnings directed at teenagers and females. Further, a better understanding of the mechanisms mediating adolescent tobacco abuse will lead to more effective treatments for young smokers who are most at risk of developing diseases caused by long-term smoking.